Humoral and cellular aspects of reticuloendothelial system (RES) host defense was studied in animals and in humans following surgery and whole-body trauma. Phagocytic activity was acutely depressed following trauma and primarily mediated by humoral opsonic deficiency as detected by bioassay. Post-trauma recovery of the RES was correlated with restoration in opsonic activity. Opsonic protein has been isolated and biochemically characterized as an alpha-2-acid glycoprotein of large molecular weight which is dependent on heparin for expression of its biological activity. A sensitive immunoassay has been developed utilizing monospecific antiserum to rat opsonic protein. Data obtained with the immunoassay correlates with opsonin levels as determined by bioassay as studied in RE blockaded rats. Acute hypoopsonemia following trauma in animals appears related to both sequestration of this glycoprotein at the site of tissue injury as well as consumption during the post-traumatic period of reticuloendothelial clearance of blood-borne particulate matter. The primary site of RES depression is the liver, with increments in pulmonary embolization of blood-borne particulate matter apparent during post-trauma RE failure. Extension of the animal studies to trauma patients revealed a similar acute humoral opsonic deficiency following injury which was more severe and persistent in non-surviving trauma patients than surviving trauma patients. While opsonin deficiency apparently mediated the acute depression of the RES, the post-traumatic generation of microthrombi and injured tissue debris can prolong the depression of the RES. Potential exists for the utilization of opsonin therapy as a means to circumvent post-surgery and post-trauma RE failure. In addition, the development of an immunoassay for clinical studies may have a significant value as a noninvasive means to monitor RE function during shock therapy.